The present invention relates to novel processes of obtaining abiraterone and derivatives, such as abiraterone acetate, in high yield and purity, as well as to novel intermediates useful in the processes.
Abiraterone acetate, the active ingredient of ZYTIGA® is the acetyl ester of abiraterone which is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Abiraterone acetate is designated chemically as (3β)-17-(3-pyridinyl)androsta-5,16-dien-3-yl acetate and its structure is:

Abiraterone acetate is manufactured by Johnson and Johnson under the brand name ZYTIGA®. An antiandrogen which is a prodrug of abiraterone, abiraterone acetate is administered as a 250 mg tablet treating metastatic castration-resistant prostate cancer. Phase III clinical trials were started in September 2010, and the results showed an overall survival rate increase of 3.9 months. Subsequently, abiraterone acetate was approved by the FDA in April 2011 after an expedited six-month review. By March 2012, production of abiraterone acetate was in excess of 2.5 tons with worldwide sales of more than $400 million.
Abiraterone acetate was discovered by Gerry Potter in 1990 at the Cancer Research UK Centre for Cancer Therapeutics within the Institute of Cancer Research in London. Commercialization rights to abiraterone acetate were assigned to British Technology Group (BTG plc), a UK company. An early route to abiraterone acetate is shown in FIG. 5 (Scheme 1, see, U.S. Pat. No. 5,604,213). Briefly, prasterone acetate 1 was treated with triflic anhydride (Tf2O) in dichloromethane (DCM) in the presence of 2,6-di-tert-butyl-4-methylpyridine (DTBMP) and afforded crude vinyl triflate 2. The resulting crude product mixture was purified via column chromatography packed with silica gel followed by recrystallization from n-hexane to provide purified vinyl triflate 2 in 58% yield. Subsequent Suzuki coupling between vinyl triflate 2 and diethyl(3-pyridyl)borane 3 was accomplished in the presence of a catalytic amount of bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2). The resulting crude product mixture was purified via silica gel column chromatography, followed by recrystallization from n-hexane. The desired abiraterone acetate was obtained in 84% yield.
Subsequent efforts were directed to isolating vinyl triflate 2 without using column chromatography (see WO2006021776A1, see FIG. 6, Scheme 2). At the same time, expensive DTBMP was replaced with a readily available base (2,6-lutidine, Et3N, or DIPEA). Despite this effort, conversion of prasterone acetate 1 was achieved in only moderate yield. As indicated by HPLC, the crude product mixture comprised about 60% of vinyl triflate 2 and about 20% of unreacted prasterone acetate 1 along with a certain amount of triene 4.
Both prasterone acetate 1 and triene 4 were difficult to remove effectively via recrystallization. The crude vinyl triflate 2 mixture was then directly taken to the subsequent Suzuki coupling with diethyl(3-pyridyl)borane 3 without purification. The resulting crude product mixture was determined to contain abiraterone acetate and unreacted prasterone acetate 1 in about a 3/1 ratio, but also containing a certain amount of triene 5. Again, both prasterone acetate 1 and diene 5 were difficult to remove efficiently via recrystallization.

BTG plc reported, however, that both prasterone acetate 1 and triene 5 could be purged successfully via a salt formation step (WO2006021776A1). The acid counterpart could be selected from hydrochloric, sulfuric, toluoyltartaric, or methanesulfonic acid (MsOH). Abiraterone acetate MsOH salt was shown to provide the best results among the four salts evaluated. Abiraterone acetate MsOH salt was preferentially prepared from a mixture of MTBE and EtOAc (FIG. 7, Scheme 3). After recrystallization from isopropyl alcohol (IPA), the purified abiraterone acetate MsOH salt was obtained in about 33% overall yield and purity was improved from 87.7% to 96.4%.
Wanle Pharmaceutical (CN102030798A) disclosed a closely related approach using trifluoromethanesulfonic acid (CF3SO3H) in place of MsOH, producing the corresponding abiraterone acetate CF3SO3H salt (FIG. 8, Scheme 4). Abiraterone acetate CF3SO3H salt was also preferentially prepared from a mixture of MTBE and EtOAc. The resulting recrystallized abiraterone acetate CF3SO3H salt was first neutralized with Na2CO3(aq) followed by recrystallization from n-hexane to generate the desired abiraterone acetate.
A different approach avoiding the use of expensive hindered base (DTBMP) as well as noxious Tf2O was described by starting with prasterone 6 as shown in FIG. 9, Scheme 5 (see U.S. Pat. No. 5,604,213 and WO 95/09178). Prasterone 6 in EtOH was combined with hydrazine monohydrate (H2NNH2—H2O) in the presence of a catalytic amount of hydrazine sulfate (H2NNH2—H2SO4) and led to hydrazone 7 in 98% yield. Vinyl iodide 8 was afforded in 90% yield after hydrazone 7 and 1,1,3,3-tetramethylquanidine (TMG) in a mixture of Et2O and THF was treated with I2.
The Suzuki reaction between vinyl iodide 8 and diethyl(3-pyridyl)borane 3 could also be achieved in the presence of a catalytic amount of Pd(PPh3)2Cl2. However, the reaction was very slow and required 2-4 days for completion. The resulting product mixture contained about 5% of dimer 10. Abiraterone 9 with a desired purity level was produced in 57% after sequential recrystallization from a mixture of MeCN/MeOH and toluene/MeOH. Crude abiraterone acetate was afforded after abiraterone 9 was treated with acetic anhydride (Ac2O) in pyridine. Reverse phase column chromatography was still required to remove the corresponding dimer 11.

Crystal Pharm (WO2013030410A2) disclosed an alternative approach leading to abiraterone 9 (FIG. 10, Scheme 6). By starting with prasterone 6, vinyl iodide 8 was obtained in 86% yield over two steps based on conditions provided in U.S. Pat. No. 5,604,213 (FIG. 9, Scheme 5). The hydroxy group in vinyl iodide 8 was transformed into its corresponding tert-butyldimethylsilyl (TBS) ether 12 in 90% yield. To silyl ether 12 was added n-BuLi under cryogenic conditions (−78° C.), and the corresponding vinyl lithium intermediate was trapped with triethyl borate followed by hydrolysis affording vinyl boronic acid 13 in 81% yield over two steps. Vinyl boronic acid 13 was coupled with 3-bromopyridine in the presence of a suitable base and a catalytic amount (6 mole %) of dichloro[1,1′-bis(diphenylphosphino)ferrocene]-palladium (II) (Pd(dppf)Cl2)-DCM in a mixture of THF and H2O at reflux temperature (ca. 70° C.). After the reaction was completed, the mixture was concentrated and diluted with EtOAc followed by addition of aqueous HCl solution affording abiraterone 9. Subsequently, the resulting abiraterone 9 HCl salt was isolated in 70% yield (49% overall yield from prasterone 6) with unknown purity.
Zach System (WO2013053691A1, see FIG. 11, Scheme 7) describes an improved method for the preparation of abiraterone 6 via prasterone formate 14, which is closely related to BTG's process. Prasterone 6 was treated with formic acid to give prasterone formate 14 quantitatively. Prasterone formate 14 was reacted with Tf2O in DCM in the presence of 2,6-lutidine afforded crude vinyl triflate 15. The reaction occurs with 80-85% conversion rate yielding 70-75% of vinyl triflate 15, 15-20% of unreacted prasterone formate 14, and <3% of diene 16. The crude mixture was taken to Suzuki cross-coupling with diethyl(3-pyridyl)borane 3 in the presence of Pd(PPh3)2Cl2 affording crude abiraterone formate 17. The resulting mixture was hydrolyzed with 10% NaOH(aq) in MeOH leading to crude abiraterone 9. Purification of crude abiraterone 9 was achieved in DCM/MeOH, and the resulting purified abiraterone 9 was generated in about 50% overall yield from prasterone 6. Subsequent acetylation of abiraterone 9 was affected in a very straight forward manner to produce abiraterone acetate in 90% yield.
CRC Center (the same applicant as U.S. Pat. No. 5,604,213) noted in Organic Preparations and Procedures Int., 29 (1), 123-134 (1997), see Scheme 5 that the palladium catalyzed cross-coupling reaction of vinyl iodide 8 with diethyl(3-pyridyl)borane 3 proceeds without the protection the 3-hydroxy function to give the abiraterone (I), whereas the use of an enol triflate (i.e. prasterone vinyl triflate (V)) in the coupling reaction did not allow this option.
Vinyl triflate 19 formation with nearly quantitative yield can be achieved by adding KHMDS (0.5M in toluene) to a hydroxy group protected prasterone 18 and PhNTf2 in THF has been reported in Steroids, 2010, 75, 936-943, see FIG. 12, Scheme 8. In this disclosed process, prasterone 18 is protected with a highly toxic protecting group (methoxymethyl, MOM, generated from carcinogen chloromethyl methyl ether (MOMCl)) which limits its use in the pharmaceutical industry. In addition, the reaction conditions of this disclosed process must be below −78° C. Moreover, the product needs to be isolated using column-chromatography.
What is needed in the art is an efficient method of preparing abiraterone and its derivatives that addresses the difficulties described by others. The present invention addresses this need, finding for example, that the use of prasterone vinyl triflate (V) in the coupling reaction is workable. Other improvements for abiraterone (I) preparation are also provided herein.